The present invention is related to computer systems for generating masks. More particularly, the invention provides systems and methods for generating and utilizing masks to form probes on a substrate.
U.S. Pat. No. 5,424,186 describes a pioneering technique for, among other things, forming and using high density arrays of molecules such as oligonucleotide, RNA, peptides, polysaccharides, and other materials. This patent is hereby incorporated by reference for all purposes. Arrays of oligonucleotides or peptides, for example, are formed on the surface by sequentially removing a photoremovable group from a surface, coupling a monomer to the exposed region of the surface, and repeating the process. These techniques have been used to form extremely dense arrays of oligonucleotides, peptides, and other materials. Such arrays are useful in, for example, drug development, oligonucleotide sequencing, oligonucleotide sequence checking, and a variety of other applications. The synthesis technology associated with this invention has come to be known as "VLSIPS" or "Very Large Scale Immobilized Polymer Synthesis" technology.
Additional techniques for forming and using such arrays are described in U.S. Pat. No. 5,384,261, which is also incorporated by reference for all purposes. Such techniques include systems for mechanically protecting portions of a substrate (or chip), and selectively deprotecting/coupling materials to the substrate. These techniques are now known as "VLSIPS II." Still further techniques for array synthesis are provided in U.S. application Ser. No. 08/327,512, also incorporated herein by reference for all purposes.
Dense arrays fabricated according to these techniques are used, for example, to screen the array of probes to determine which probe(s) are complementary to a target of interest. According to one specific aspect of the inventions described above, the array is exposed to a labeled target. The target may be labeled with a wide variety of materials, but an exemplary label is a fluorescein label. The array is then scanned with a confocal microscope based detection system, or other related system, to identify where the target has bound to the array. Other labels include, but are not limited to, radioactive labels, large molecule labels, and others.
While meeting with dramatic success, such methods meet with limitations in some circumstances. For example, during the design of the layout of molecules in an array according to the above techniques, it is necessary to design a "mask" that will define the locations on a substrate that are exposed to light. While such masks are easily fabricated, they tend to be costly. The design of such masks is described in U.S. Pat. No. 5,571,639, incorporated herein by reference for all purposes.
Often it is desirable to have a specific layout of molecules in an array for a particular application. For example, PCT WO95/11995, which is incorporated by reference for all purposes, describes the synthesis of particular arrays for use in HIV diagnostics, the diagnosis of genes relevant to certain cancers, evaluation of the mitochondrial oligonucleotide, and other applications. In many of these applications there is demand for a large volume of identical chips, such as in HIV diagnostics. In many situations, the manufacture of a particular probe array will require a mask (or mask set) with as many as one hundred reticles or more. The cost of masks in these situations, while high on a per mask basis, becomes quite small when viewed in light of the number of identical arrays that may be synthesized with a particular mask.
However, in many other applications, such as particular research applications, it is desirable to synthesize a relatively small number of arrays with a particular layout of probes, perhaps as few as a single array. While this is certainly possible and has found wide utility in the art, it is costly to fabricate a single mask (or mask set) for the manufacture of only a few probe arrays. Accordingly, the "per chip" cost of masks in these situations can be quite high (on the order of thousands of dollars).
Accordingly, it is desirable to identify more efficient techniques for designing and using lithographic masks in the manufacture of probe arrays and, in particular, reduce the number of reticles required for a low volume design.